The research conducted on the pyrrolizidine alkaloids during the year will be related to the isolation and identification of the active metabolite (s) responsible for the hepatic and cardiopulamonary lesions. These metabolites will be synthesized and their interaction with protein and nucleic acids of affected cells evaluated. There are preliminary data indicating that the covalent binding of metabolites of the pyrrolizidine alkaloids are responsible for many of the lesions that occur in exposed mammals. It will be necessary to conduct this research in nonhuman primates and rats in that there are strong indications that different metbolic pathways for the pyrrolizidine alkaloids are present in these two species. Age of the animal also will be considered in evaluating these metabolites of the pyrrolizidine alkaloids. There are data which indicate that infants are more susceptible to the development of cardiopulmonary lesions while adults usually succumb to hepatic lesions. These differences are likely related to the metabolism of the alkaloids. Since it has not been possible to date to label the pyrrolizidine ring moiety a semisynthetic pyrrolizidine alkaloid has been labeled with 3H at 1 methyl proton, This semisynthetic pyrrolizidine alkaloid has been shown to produce lesions identical to the naturally occurring ones. Through the use of this radioactive pyrrolizidine alkaloids, it will be possible to more readily identify the active metabolites and their interaction with tissue macromolecules.